Carnathan Diane G, Wetzel Katherine S, Yu Joana, Lee S Thera, Johnson Brent A, Paiardini Mirko, Yan Jian, Morrow Matthew P, Sardesai Niranjan Y, Weiner David B, Ertl Hildegund C J, Silvestri Guido
Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
Department of Biostatistics and Computational Biology, University of Rochester, Rochester, NY 14642;
Proc Natl Acad Sci U S A. 2015 Jan 13;112(2):518-23. doi: 10.1073/pnas.1407466112. Epub 2014 Dec 30.
An effective T-cell-based AIDS vaccine should induce strong HIV-specific CD8(+) T cells in mucosal tissues without increasing the availability of target cells for the virus. Here, we evaluated five immunization strategies that include Human adenovirus-5 (AdHu5), Chimpanzee adenovirus-6 (AdC6) or -7 (AdC7), Vaccinia virus (VV), and DNA given by electroporation (DNA/EP), all expressing Simian immunodeficiency virus group specific antigen/transactivator of transcription (SIV(mac239Gag/Tat)). Five groups of six rhesus macaques (RMs) each were vaccinated with DNA/EP-AdC6-AdC7, VV-AdC6-AdC7, DNA/-EP-VV-AdC6, DNA/EP-VV-AdC7, or AdHu5-AdHu5-AdHu5 and were challenged repeatedly with low-dose intrarectal SIVmac239. Upon challenge, there were no significant differences among study groups in terms of virus acquisition or viral load after infection. When taken together, the immunization regimens did not protect against SIV acquisition compared with controls but did result in an ∼ 1.6-log decline in set-point viremia. Although all immunized RMs had detectable SIV-specific CD8(+) T cells in blood and rectal mucosa, we found no correlation between the number or function of these SIV-specific CD8(+) T cells and protection against SIV acquisition. Interestingly, RMs experiencing breakthrough infection showed significantly higher prechallenge levels of CD4(+)C-C chemokine receptor type 5 (CCR5)(+)HLA-DR(+) T cells in the rectal biopsies (RB) than animals that remained uninfected. In addition, among the infected RMs, the percentage of CD4(+)CCR5(+)Ki-67(+) T cells in RBs prechallenge correlated with higher early viremia. Overall, these data suggest that the levels of activated CD4(+)CCR5(+) target T cells in the rectal mucosa may predict the risk of SIV acquisition in RMs vaccinated with vectors that express SIVGag/Tat.
一种有效的基于T细胞的艾滋病疫苗应在黏膜组织中诱导产生强大的HIV特异性CD8(+) T细胞，同时不增加病毒的靶细胞可用性。在此，我们评估了五种免疫策略，包括人腺病毒5型（AdHu5）、黑猩猩腺病毒6型（AdC6）或7型（AdC7）、痘苗病毒（VV）以及通过电穿孔给予的DNA（DNA/EP），所有这些都表达猴免疫缺陷病毒组特异性抗原/转录激活因子（SIV(mac239Gag/Tat)）。将五组，每组六只恒河猴（RM）分别用DNA/EP-AdC6-AdC7、VV-AdC6-AdC7、DNA/-EP-VV-AdC6、DNA/EP-VV-AdC7或AdHu5-AdHu5-AdHu5进行免疫接种，并用低剂量直肠内SIVmac239反复攻击。在攻击后，各研究组在病毒感染或感染后的病毒载量方面没有显著差异。综合来看，与对照组相比，免疫方案并不能预防SIV感染，但确实导致设定点病毒血症下降了约1.6个对数。尽管所有免疫接种的恒河猴在血液和直肠黏膜中都有可检测到的SIV特异性CD8(+) T细胞，但我们发现这些SIV特异性CD8(+) T细胞的数量或功能与预防SIV感染之间没有相关性。有趣的是，经历突破性感染的恒河猴在直肠活检（RB）中，攻击前CD4(+) C-C趋化因子受体5型（CCR5）(+) HLA-DR(+) T细胞的水平显著高于未感染的动物。此外，在感染的恒河猴中，攻击前RB中CD4(+) CCR5(+) Ki-67(+) T细胞的百分比与较高的早期病毒血症相关。总体而言，这些数据表明，直肠黏膜中活化的CD4(+) CCR5(+)靶T细胞水平可能预测接种表达SIVGag/Tat载体的恒河猴感染SIV的风险。
